As an approach to protection against a Herpes Simplex Virus (HSV) infection, synthetic peptides of known secondary structure with amino acid sequences matching the first 23 NH2 terminal amino acids of glycoprotein D (gD) of HSV-1 and HSV-2 were employed to immunize mice. One impressive finding has been the ability of these synthetic peptides to protect against a lethal challenge infection with HSV-2 in mice. Since virus neutralizing titers of sera obtained from mice immunized with synthetic peptides were in some cases low, it was suggested that stimulation of T cells rather than induction of neutralizing antibody is responsible for conferring immunity against a lethal infection with HSV. In order to investigate the T cell response to these peptides, lymph node T cells from mice immunized with a single dose of synthetic peptide were examined for their ability to proliferate specifically in response to antigen and antigen-presenting cells (APC). The synthetic peptide 1-23(H) induced the production of T lymphocytes which proliferate specifically in the presence of syngeneic APC and this peptide. The fine specificity of the T cell response was determined by stimulating with overlapping peptides within residues 1-23 of the gD sequence. The response pattern varied from strain to strain. The B10.A preferred the C-terminal region whereas the B10 and B10.A(5R) preferred the NH2 terminal region of the 1-23 synthetic peptide. The fact that B10 and B10.A(5R) share the I-Ab haplotype strongly indicates that the MHC is involved in the control of T cell fine specificity. We also examined the role of peptide secondary structure in the T cell response to these antigens. Circular dichroism measurements were made in TFE, a helix promoting solvent, and the per cent helicity determined. We were able to show a striking relationship between secondary structure and the specificity of the T cells. Thus, T cells immunized with helical peptides recognized helical but not nonhelical structures and vice versa. We also found that helical or nonhelical structures adjacent to the determinant could predictably modify the response to the determinant. From the data obtained we conclude that there are several T cell immunodominant regions under Ir gene control within residues 1-23 of the gD molecule. Our intention is to evaluate these structurally defined T cell regions for their significance in the immunological events which cause protection against lethal HSV infections.